title: Integrins protect cardiomyocytes from ischemia/reperfusion injury.
abstract: Ischemic damage is recognized to cause cardiomyocyte (CM) death and myocardial dysfunction, but the role of cell-matrix interactions and integrins in this process has not been extensively studied. Expression of α7β1D integrin, the dominant integrin in normal adult CMs, increases during ischemia/reperfusion (I/R), while deficiency of β1 integrins increases ischemic damage. We hypothesized that the forced overexpression of integrins on the CM would offer protection from I/R injury. Tg mice with CM-specific overexpression of integrin α7β1D exposed to I/R had a substantial reduction in infarct size compared with that of α5β1D-overexpressing mice and WT littermate controls. Using isolated CMs, we found that α7β1D preserved mitochondrial membrane potential during hypoxia/reoxygenation (H/R) injury via inhibition of mitochondrial Ca2+ overload but did not alter H/R effects on oxidative stress. Therefore, we assessed Ca2+ handling proteins in the CM and found that β1D integrin colocalized with ryanodine receptor 2 (RyR2) in CM T-tubules, complexed with RyR2 in human and rat heart, and specifically bound to RyR2 amino acids 165-175. Integrins stabilized the RyR2 interdomain interaction, and this stabilization required integrin receptor binding to its ECM ligand. These data suggest that α7β1D integrin modifies Ca2+ regulatory pathways and offers a means to protect the myocardium from ischemic injury.
authors.forename: Hideshi
authors.initials: H
authors.lastname: Okada
authors.forename: N Chin
authors.initials: NC
authors.lastname: Lai
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Kawaraguchi
authors.forename: Peter
authors.initials: P
authors.lastname: Liao
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Copps
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Sugano
authors.forename: Sunaho
authors.initials: S
authors.lastname: Okada-Maeda
authors.forename: Indroneal
authors.initials: I
authors.lastname: Banerjee
authors.forename: Jan M
authors.initials: JM
authors.lastname: Schilling
authors.forename: Alexandre R
authors.initials: AR
authors.lastname: Gingras
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Asfaw
authors.forename: Jorge
authors.initials: J
authors.lastname: Suarez
authors.forename: Seok-Min
authors.initials: SM
authors.lastname: Kang
authors.forename: Guy A
authors.initials: GA
authors.lastname: Perkins
authors.forename: Carol G
authors.initials: CG
authors.lastname: Au
authors.forename: Sharon
authors.initials: S
authors.lastname: Israeli-Rosenberg
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Manso
authors.forename: Zheng
authors.initials: Z
authors.lastname: Liu
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Milner
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Kaufman
authors.forename: Hemal H
authors.initials: HH
authors.lastname: Patel
authors.forename: David M
authors.initials: DM
authors.lastname: Roth
authors.forename: H Kirk
authors.initials: HK
authors.lastname: Hammond
authors.forename: Susan S
authors.initials: SS
authors.lastname: Taylor
authors.forename: Wolfgang H
authors.initials: WH
authors.lastname: Dillmann
authors.forename: Joshua I
authors.initials: JI
authors.lastname: Goldhaber
authors.forename: Robert S
authors.initials: RS
authors.lastname: Ross
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015687:Cell Hypoxia; D002478:Cells, Cultured; D006801:Humans; D016023:Integrins / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D021122:Protein Subunits / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019837:Ryanodine Receptor Calcium Release Channel / Q000737:chemistry / Q000378:metabolism
chemical_list: D016023:Integrins; D010446:Peptide Fragments; D021122:Protein Subunits; D019837:Ryanodine Receptor Calcium Release Channel; C082908:integrin alpha7beta1; D002118:Calcium